U.S. patent number 11,124,513 [Application Number 16/328,117] was granted by the patent office on 2021-09-21 for avibactam free acid.
This patent grant is currently assigned to Sandoz AG. The grantee listed for this patent is Sandoz AG. Invention is credited to Michael Fischer, Andreas Lechner, Brigitte Staggl.
United States Patent |
11,124,513 |
Fischer , et al. |
September 21, 2021 |
Avibactam free acid
Abstract
The present invention relates to avibactam free acid, a method
for preparing avibactam free acid and a method for preparing
avibactam sodium by further reacting avibactam free acid. The
invention further refers to a pharmaceutical composition comprising
avibactam free acid, one or more alkaline sodium salt(s) and one or
more beta-lactam antibiotic(s). The pharmaceutical composition of
the present invention can be used as medicament, in particular for
treatment and/or prevention of bacterial infections.
Inventors: |
Fischer; Michael (Kundl,
AT), Lechner; Andreas (Kundl, AT), Staggl;
Brigitte (Kundl, AT) |
Applicant: |
Name |
City |
State |
Country |
Type |
Sandoz AG |
Basel |
N/A |
CH |
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Assignee: |
Sandoz AG (Basel,
CH)
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Family
ID: |
56802364 |
Appl.
No.: |
16/328,117 |
Filed: |
August 25, 2017 |
PCT
Filed: |
August 25, 2017 |
PCT No.: |
PCT/EP2017/071471 |
371(c)(1),(2),(4) Date: |
February 25, 2019 |
PCT
Pub. No.: |
WO2018/037124 |
PCT
Pub. Date: |
March 01, 2018 |
Prior Publication Data
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Document
Identifier |
Publication Date |
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US 20190185473 A1 |
Jun 20, 2019 |
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Foreign Application Priority Data
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Aug 26, 2016 [EP] |
|
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16185913 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P
31/04 (20180101); C07D 471/08 (20130101); C07B
2200/13 (20130101) |
Current International
Class: |
A61K
31/4188 (20060101); C07D 471/08 (20060101); A61P
31/04 (20060101); A61K 31/439 (20060101) |
References Cited
[Referenced By]
U.S. Patent Documents
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7112592 |
September 2006 |
Lampilas et al. |
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Foreign Patent Documents
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106699756 |
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May 2017 |
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CN |
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2002010172 |
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Feb 2002 |
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WO |
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2011042560 |
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Apr 2011 |
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WO |
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2012172368 |
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Dec 2012 |
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WO |
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2014135930 |
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Sep 2014 |
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WO |
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2017025526 |
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Feb 2017 |
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WO |
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Other References
Database Chemcats, Chemical Abstracts Service, Columbus, Ohio, Feb.
23, 2015. cited by applicant .
International Search Report and Written Opinion for
PCT/EP2017/071471, dated Dec. 18, 2017, 20 pages. cited by
applicant .
New Drug Application (NDA) 206494, Submission Suppl-1:
Labeling-Package Insert AVYCAZ, Sep. 2, 2015, pp. 1-20. cited by
applicant.
|
Primary Examiner: Coleman; Brenda L
Attorney, Agent or Firm: Luedeka Neely Group, P.C.
Claims
The invention claimed is:
1. A crystalline form of
[(2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl]
hydrogen sulfate according to Formula (I) ##STR00008##
characterized by a powder X-ray diffractogram comprising
reflections at 2-Theta angles of (9.6.+-.0.2.degree.),
(11.1.+-.0.2.degree.) and (17.4.+-.0.2.degree.) or, a powder X-ray
diffractogram comprising reflections at 2-Theta angles of
(9.3.+-.0.2.degree.), (10.1.+-.0.2.degree.) and
(16.7.+-.0.2.degree.), when measured with CuKalpha1,2 radiation
having a wavelength of 0.15419 nm.
2. The crystalline form of
[(2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl]
hydrogen sulfate according to claim 1 characterized by (i) having a
powder X-ray diffractogram comprising reflections at 2-Theta angles
of (9.6.+-.0.2.degree.), (11.1.+-.0.2.degree.) and
(17.4.+-.0.2.degree.), when measured with CuKalpha.sub.1,2
radiation having a wavelength of 0.15419 nm; and/or (ii) having a
Fourier transform infrared spectrum comprising peaks at wavenumbers
of (3391.+-.2) cm.sup.-1, (1820.+-.2) cm.sup.-1 and (1688.+-.2)
cm.sup.-1, when measured with a diamond ATR cell.
3. The crystalline form of
[(2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl]
hydrogen sulfate according to claim 1 characterized by (i) having a
powder X-ray diffractogram comprising reflections at 2-Theta angles
of (9.3.+-.0.2.degree.), (10.1.+-.0.2.degree.) and
(16.7.+-.0.2.degree.), when measured with CuKalpha.sub.1,2
radiation having a wavelength of 0.15419 nm; and/or (ii) having a
Fourier transform infrared spectrum comprising peaks at wavenumbers
of (3403.+-.2) cm.sup.-1, (1825.+-.2) cm.sup.-1 and (1686.+-.2)
cm.sup.-1, when measured with a diamond ATR cell.
4. The crystalline form of
[(2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl]
hydrogen sulfate according to Formula (I) according to claim 1
having a purity of at least 95%.
5. A method for the preparation of the crystalline form of
[(2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl]
hydrogen sulfate according to Formula (I) as defined in claim 1
comprising: (a) reacting a compound according to Formula (II)
##STR00009## wherein M.sup..sym. is N.sup..sym.RR'R''R''' with R,
R', R'' and R''' each being independently selected from hydrogen
and an alkyl group with 1 to 6 carbon atoms, with one or more
acid(s) having a pKa<-1; and (b) optionally isolating at least a
part of the compound according to Formula (I).
6. The method according to claim 5, wherein M.sup..sym. is
N.sup..sym.RR'R''R''' with R, R', R'' and R''' each being
n-butyl.
7. The method according to claim 5, wherein the acid having a
pKa<-1 is selected from the group consisting of hydrochloric
acid, nitric acid and p-toluene sulfonic acid.
8. A pharmaceutical composition comprising a solid crystalline form
of [(2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl]
hydrogen sulfate according to Formula (I) ##STR00010##
characterized by a powder X-ray diffractogram comprising
reflections at 2-Theta angles of (9.6.+-.0.2.degree.),
(11.1.+-.0.2.degree.) and (17.4.+-.0.2.degree.) or, a powder X-ray
diffractogram comprising reflections at 2-Theta angles of
(9.3.+-.0.2.degree.), (10.1.+-.0.2.degree.) and
(16.7.+-.0.2.degree.), when measured with CuKalpha1,2 radiation
having a wavelength of 0.15419 nm.
9. A pharmaceutical composition comprising an effective and/or
predetermined amount of the solid crystalline form of
[(2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl]
hydrogen sulfate according to Formula (I) as defined in claim 1,
one or more alkaline sodium salt(s) and one or more beta-lactam
antibiotics selected from the group consisting of ceftazidime,
ceftaroline fosamil and piperacillin.
10. The pharmaceutical composition according to claim 9, wherein
the one or more alkaline sodium salt(s) is selected from sodium
carbonate and sodium hydrogen carbonate.
11. The pharmaceutical composition according to claim 9, wherein
the one or more beta-lactam antibiotics is selected from the group
consisting of ceftazidime and piperacillin.
12. A method for treating bacterial infections comprising
administering an effective amount of the crystalline form of
[(2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl]
hydrogen sulfate according to claim 1.
13. A method for preparing the compound according to Formula (III)
##STR00011## comprising (a) reacting a crystalline form of
[(2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl]
hydrogen sulfate according to Formula (I) ##STR00012##
characterized by a powder X-ray diffractogram comprising
reflections at 2-Theta angles of (9.6.+-.0.2.degree.),
(11.1.+-.0.2.degree.) and (17.4.+-.0.2.degree.) or, a powder X-ray
diffractogram comprising reflections at 2-Theta angles of
(9.3.+-.0.2.degree.), (10.1.+-.0.2.degree.) and
(16.7.+-.0.2.degree.), when measured with CuKalpha1,2 radiation
having a wavelength of 0.15419 nm, with one or more sodium salt(s)
of an organic acid having 2 to 8 carbon atoms; and (b) optionally
isolating at least a part of the compound according to Formula
(III).
14. The method according to claim 13, wherein the sodium salt of
the organic acid having 2 to 8 carbon atoms is sodium
2-ethylhexanoate.
Description
This application is a Section 371 national phase entry of PCT
application PCT/EP2017/071471, filed Aug. 25, 2017. This
application also claims the benefit of the earlier filing date of
European patent application 16185913.7, filed Aug. 26, 2016.
FIELD OF THE INVENTION
The present invention relates to avibactam free acid, a method for
preparing avibactam free acid and a method for preparing avibactam
sodium by further reacting avibactam free acid. The invention
further refers to a pharmaceutical composition comprising avibactam
free acid, one or more alkaline sodium salt(s) and one or more
beta-lactam antibiotic(s). The pharmaceutical composition of the
present invention can be used as medicament, in particular for
treatment and/or prevention of bacterial infections.
BACKGROUND OF THE INVENTION
The IUPAC name of avibactam is
[(2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicylco[3.2.1]octan-6-yl]
hydrogen sulfate. Avibactam is represented by the following
chemical structure according to Formula (I):
##STR00001##
Avibactam is a non-beta-lactam beta-lactamase inhibitor which is
reported to have in itself no antibacterial activity at clinically
relevant doses. However, avibactam protects beta-lactam antibiotics
from degradation by beta lactamase enzymes and therefore maintains
the antibacterial activity of beta-lactam antibiotics. It is
therefore useful in conjunction with beta-lactam antibiotics for
the treatment of bacterial infections.
WO 02/10172 A1 describes a synthesis pathway for avibactam sodium,
which is obtained by subjecting the avibactam tetrabutylammonium
salt to an ion exchange resin (DOWEX 50WX8 sodium form). Albeit
mentioning also avibactam in form of the free acid, said document
does neither provide a method for its preparation let alone any
analytical data of avibactam free acid.
WO 2012/172368 A1 describes an alternative method of preparing
avibactam sodium without the need of an ion exchange resin.
According to the document, avibactam sodium can be obtained by
reacting avibactam tetrabutylammonium salt with sodium
2-ethylhexanoate. Again no disclosure of avibactam free acid and
its preparation is provided.
However, it was found by the inventors of the present invention
that the chemical purity of the obtained avibactam sodium is solely
determined by the chemical purity of the employed
tetrabutylammonium salt, because the process according to WO
2012/172368 possesses no purification effect.
Hence, one objective of the present invention was the provision of
an improved process for the preparation of avibactam sodium, in
particular a process which allows for the preparation of highly
pure avibactam sodium regardless of the quality of the applied
avibactam tetrabutylammonium salt.
In addition, WO 2011/042560 A1 refers to crystalline forms of
avibactam sodium. For example, WO 2011/042560 A1 discloses
anhydrous forms B and D as well as hydrated forms A and E. In
addition, according to the application (page 3, lines 6 to 7) a
fifth form designated "form C" has been observed but only as a
mixture with form A. Specifically, WO 2011/042560 A1 explicitly
states that "Form C is not isolated as a pure form but is obtained
in a mixture with one or more other forms, in particular Form A"
(page 12, lines 5-7). However, the application does not provide any
teaching on how to prepare any such mixture.
Finally, also WO 2014/135930 A1 discloses a crystalline form of
avibactam sodium characterized by powder X-ray diffraction.
According to the peak list provided on page 6 and the corresponding
powder X-ray diffractogram displayed in FIG. 1 of said application
this solid can be assigned to a mixture comprising form B and form
D of WO 2011/042560 A1.
WO 2017/025526 relates to crystalline form C of avibactam sodium,
especially in polymorphically pure or essentially polymorphically
pure form as well as to an industrially applicable, reliable and
robust process for its preparation and to pharmaceutical
compositions thereof. This document represents the first disclosure
for the reliable preparation and isolation of polymorphically pure
form C of Avibactam sodium.
It is well-known by the skilled person that upon temperature stress
or under acidic or basic conditions hydrated forms often tend to
hydrolyze. Hydrates are also prone to dehydration, for example,
they readily lose their water when subjected to dry conditions
and/or increased temperatures. For example, WO 2011/042560 A1
mentions that form E tends to lose water and to hydrolyze (page 17
lines 1 to 2). It is further stated in the application that the
avibactam sodium dihydrate form E is particularly stable above
relative humidities of about 70%, indicating that this hydrated
form is only stable in the presence of moisture. In addition, it
was found that form E dehydrates to the monohydrate form A at
temperatures above about 60.degree. C. and that form A upon further
temperature stress dehydrates to the anhydrous form B. This is
critical as particular pharmaceutical processing steps such as
milling and drying usually involve the evolution of heat and
therefore may trigger solid form transformations of thermally
labile forms. Hence, for pharmaceutical purposes anhydrous forms of
avibactam and its pharmaceutically acceptable salts are preferred
over hydrates.
However, also the anhydrous forms of avibactam sodium disclosed in
WO 2011/042560 A1 suffer from certain drawbacks with regard to
their physical properties and manufacturability respectively. For
example it was surprisingly found by the inventors of the present
invention that both forms B and D of avibactam sodium are not
stable in the presence of moisture but significantly absorb water
and undergo phase transformations, e.g. to hydrate form A, when
subjected to increased relative humidity levels.
Besides proper physical properties, the manufacturability of a
solid form determines, whether it is a feasible candidate for the
preparation of a drug product. According to WO 2011/042560 A1 (page
16, lines 30 to 31) anhydrous form D was only obtained as very
small crystals, making filtration difficult and slow. Hence, due to
its limitations with regards to isolation, form D cannot be
produced on industrial scale. Usually, bulk materials consisting of
such small crystals also show unsatisfactory powder properties such
as bad flowability and compaction properties. In addition, the
robustness and reliability of a manufacturing process is a key
criterion for physical form selection. WO 2011/042560 A1 (page 17,
lines 8 to 14) for example mentions that anhydrous form B is
difficult to prepare and only obtained in a very narrow range of
water activity. Therefore, a reliable industrial production of
anhydrous form B seems to be rather challenging according to the
teaching of WO 2011/042560 A1.
A further objective of the present invention was therefore the
provision of an improved form of avibactam, which is physically and
chemically stable, i.e. which does not chemically degrade and/or
convert to other solid forms during pharmaceutical processing
and/or upon storage. An additional objective of the invention was
to provide an improved form of avibactam, which possesses improved
powder properties such as high bulk density, good flowability and
no dusting and is thus more convenient to handle during
pharmaceutical processing. It was a further objective of the
present invention to provide an improved form of avibactam, which
can be reliably and routinely manufactured also on industrial
scale. Furthermore, it was an objective to provide a solid
pharmaceutical composition comprising an improved form of
avibactam, which is chemically and physically stable upon storage
under various conditions e.g. at ambient conditions.
SUMMARY OF THE INVENTION
The present invention solves one or more of the aforementioned
problems by providing avibactam in form of its free acid. Avibactam
free acid of the present invention is of low hygroscopicity and
stable against moisture and temperature stress. In addition,
avibactam of the present invention shows advantageous morphology,
homogenous particle size distribution and consequently is
characterized by excellent powder properties such as bulk density,
flowability and compactability, and shows no dusting.
Hence, in a first aspect the invention relates to
[(2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicylco[3.2.1]octan-6-yl]
hydrogen sulfate (avibactam), preferably being present in
crystalline form.
The present invention also relates to a method of preparing
[(2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicylco[3.2.1]octan-6-yl]
hydrogen sulfate (avibactam).
The present invention also concerns a pharmaceutical composition
comprising an effective and/or predetermined amount of
[(2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicylco[3.2.1]octan-6-yl]
hydrogen sulfate (avibactam), one or more alkaline sodium salt(s)
and one or more beta-lactam antibiotic(s) and to said
pharmaceutical composition for use as medicament in particular for
treatment and/or prevention of bacterial infections. A method for
preparing said pharmaceutical composition is also subject-matter of
the present invention.
It was surprisingly found, that avibactam in form of its free acid
is obtained in high purity and therefore represents an excellent
means for purification. E.g. when reacting avibactam
tetrabutylammonium salt to avibactam free acid of the present
invention and further reacting the free acid to the sodium salt,
the final avibactam sodium is obtained in high chemical purity
regardless the quality of the applied tetrabutylammonium salt. This
is in contrast to the previously described process wherein
avibactam sodium is directly prepared from the tetrabutylammonium
salt, where the purity of the obtained product is directly
dependent on the chemical purity of the employed tetrabutylammonium
salt, said process showing no purification effect.
Hence, the present invention also relates to the use of
[(2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicylco[3.2.1]octan-6-yl]
hydrogen sulfate (avibactam) for the preparation of avibactam
salts, in particular avibactam sodium.
Finally, another aspect of the invention concerns a method for
preparing avibactam sodium from
[(2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicylco[3.2.1]octan-6-yl]
hydrogen sulfate (avibactam).
Definitions
Unless indicated otherwise the terms used herein have the following
meanings:
As used herein the term "avibactam" refers to
[(2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicylco[3.2.1]octan-6-yl]
hydrogen sulfate which can be represented by the chemical structure
according to Formula (I) herein. In the present invention
"avibactam" indicates the free acid form, where the hydrogen atom
of the sulfuric acid group is not substituted by another kind of
atom, for example by sodium or potassium.
As used herein the term "room temperature" refers to a temperature
in the range of from 20 to 30.degree. C.
The term "reflection" with regards to powder X-ray diffraction as
used herein, means peaks in an X-ray diffractogram, which are
caused at certain diffraction angles (Bragg angles) by constructive
interference from X-rays scattered by parallel planes of atoms in
solid material, which are distributed in an ordered and repetitive
pattern in a long-range positional order. Such a solid material is
classified as crystalline material, whereas amorphous material is
defined as solid material, which lacks long-range order and only
displays short-range order, thus resulting in broad scattering.
According to literature, long-range order e.g. extends over
approximately 10.sup.3 to 10.sup.20 atoms, whereas short-range
order is over a few atoms only (see "Fundamentals of Powder
Diffraction and Structural Characterization of Materials" by
Vitalij K. Pecharsky and Peter Y. Zavalij, Kluwer Academic
Publishers, 2003, page 3).
The term "essentially the same" with reference to powder X-ray
diffraction means that variabilities in peak positions and relative
intensities of the peaks are to be taken into account. For example,
a typical precision of the 2-Theta values is in the range of
.+-.0.2.degree. 2-Theta. Thus, a diffraction peak that usually
appears at 6.5.degree. 2-Theta for example can appear in the range
of from 6.3.degree. to 6.7.degree. 2-Theta on most X-ray
diffractometers under standard conditions. Furthermore, one skilled
in the art will appreciate that relative peak intensities will show
inter-apparatus variability as well as variability due to degree of
crystallinity, preferred orientation, sample preparation and other
factors known to those skilled in the art and should be taken as
qualitative measure only.
The term "essentially the same" with reference to Fourier transform
infrared spectroscopy means that variabilities in peak positions
and relative intensities of the peaks are to be taken into account.
For example, a typical precision of the wavenumbers is in the range
of .+-.2 cm.sup.-1. Thus, a peak that usually appears at 1820
cm.sup.-1 can appear in the range of from 1818 to 1822 cm.sup.-1 on
most infrared spectrometers under standard conditions. Furthermore,
one skilled in the art will appreciate that relative peak
intensities will show inter-apparatus variability as well as
variability due to degree of crystallinity, sample preparation and
other factors known to those skilled in the art and should be taken
as qualitative measure only.
The term "solid form" as used herein refers to any crystalline and
amorphous phase of a material.
The term "form A" or "crystalline form A" as used herein refers to
the crystalline monohydrate of avibactam sodium disclosed in WO
2011/042560 A1 which is characterized by having a PXRD comprising
reflections at 2-Theta angles of (8.5.+-.0.2).degree.,
(15.3.+-.0.2).degree. and (16.4.+-.0.2).degree., when measured with
Cu-Kalpha.sub.1,2 radiation having a wavelength of 0.15419 nm.
The term "form B" or "crystalline form B" as used herein refers to
the crystalline form of avibactam sodium disclosed in WO
2011/042560 A1 which is characterized by having a PXRD comprising
reflections at 2-Theta angles of (13.0.+-.0.2).degree.,
(16.5.+-.0.2).degree., (17.2.+-.0.2).degree., when measured with
Cu-Kalpha.sub.1,2 radiation having a wavelength of 0.15419 nm.
The term "form D" or "crystalline form D" as used herein refers to
the crystalline form of avibactam sodium disclosed in WO
2011/042560 A1 which is characterized by having a PXRD comprising
reflections at 2-Theta angles of (12.4.+-.0.2).degree.,
(16.2.+-.0.2).degree., (17.4.+-.0.2).degree.,
(17.8.+-.0.2).degree., (18.5.+-.0.2).degree. and
(22.2.+-.0.2).degree., when measured with Cu-Kalpha.sub.1,2
radiation having a wavelength of 0.15419 nm.
The term "form C" or "crystalline form C" as used herein refers to
the crystalline form of avibactam sodium disclosed in WO
2017/025526 A1 which is characterized by having a PXRD comprising
reflections at 2-Theta angles of (6.5.+-.0.2).degree.,
(14.4.+-.0.2).degree., (15.5.+-.0.2).degree., (18.0.+-.0.2).degree.
and (19.3.+-.0.2).degree., when measured at room temperature with
Cu-Kalpha.sub.1,2 radiation having a wavelength of 0.15419 nm.
The term "about" as used herein means within 5%, more typically
within 1% and most typically within 0.5% of the indicated value or
range.
The term "treating bacterial infections" as used herein includes
the cure, prevention and/or amelioration of conditions directly or
indirectly caused by bacteria, in particular beta-lactamase
producing bacteria.
The term "predetermined amount" of avibactam as used herein refers
to the amount of avibactam which is present in a composition, e.g.
a pharmaceutical composition, at the time of preparing said
composition.
The term "effective amount" of avibactam as used herein means an
amount sufficient to provide a therapeutic benefit in the treatment
of a disease or disorder, or to delay or minimize one or more
symptoms associated with the disease or disorder.
As used herein the term "isolated" with reference to avibactam
corresponds to avibactam that is physically separated from the
reaction mixture in which it is formed.
As used herein the term "plates" or "plate-like" with regards to
particle or crystal shape refers to flat, tabular particles or
crystals which have similar breadth and width.
The term "laths" as used herein with regards to particle or crystal
shape refers to elongated, thin and blade-like particles or
crystals.
The term "agitation" as used herein relates to any motion of a
macroscopic constituent of a solution or suspension which is
induced from outside, relative to another macroscopic constituent
of the solution or suspension. The term "mechanical agitation" as
used herein relates to any motion of a macroscopic constituent of a
solution or suspension which is induced from outside via a device,
such as shaking or stirring or sonication, relative to another
macroscopic constituent of the solution. The term "stirring" as
used herein relates to any motion of a macroscopic constituent of a
solution or suspension which is induced from outside via a stirring
device, relative to another macroscopic constituent of the solution
or suspension.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1: illustrates a representative powder X-ray diffractogram of
the crystalline form (Form 1) of avibactam according to the present
invention. The x-axis shows the scattering angle in
.degree.2-theta, the y-axis shows the intensity of the scattered
X-ray beam in counts of detected photons.
FIG. 2: illustrates a representative Fourier transform infrared
spectrum in transmission mode of the crystalline form (Form 1) of
avibactam according to the present invention. The x-axis shows the
frequency in wavenumbers (cm.sup.-1), the y-axis shows the relative
intensity of the peaks in percent (%).
FIG. 3: illustrates a representative differential scanning
calorimetry curve of the crystalline form (Form 1) of avibactam
according to the present invention in the temperature range of from
25 to 130.degree. C. The x-axis shows the temperature in degree
Celsius (.degree. C.), the y-axis shows the heat flow rate in Watt
per gram (W/g) with endothermic peaks going up.
FIG. 4: illustrates a representative thermogravimetric analysis
curve of the crystalline form (Form 1) of avibactam according to
the present invention in the temperature range of from 25 to
130.degree. C. The x-axis shows the temperature in degree Celsius
(.degree. C.), the y-axis shows the mass (loss) of the sample in
weight percent (weight %).
FIG. 5a: illustrates a scanning electron microscopic image of the
crystalline form (Form 1) of avibactam according to the present
invention.
FIG. 5b: illustrates a scanning electron microscopic image of
crystalline form B of avibactam sodium according to WO 2011/042560
A1.
FIG. 5c: illustrates a scanning electron microscopic image of
crystalline form D of avibactam sodium according to WO 2011/042560
A1.
FIG. 6: illustrates a representative powder X-ray diffractogram of
the crystalline form (Form 2) of avibactam according to the present
invention. The x-axis shows the scattering angle in
.degree.2-theta, the y-axis shows the intensity of the scattered
X-ray beam in counts of detected photons.
FIG. 7: illustrates a representative Fourier transform infrared
spectrum in transmission mode of the crystalline form (Form 2) of
avibactam according to the present invention. The x-axis shows the
frequency in wavenumbers (cm.sup.-1), the y-axis shows the relative
intensity of the peaks in percent (%).
DETAILED DESCRIPTION OF THE INVENTION
Different aspects of the invention are described below in further
detail by embodiments, without being limited thereto. Each aspect
of the invention may be described by one embodiment or by combining
two or more embodiments.
In a first aspect the invention relates to
[(2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicylco[3.2.1]octan-6-yl]
hydrogen sulfate according to Formula (I)
##STR00002##
In one embodiment the present invention relates to
[(2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicylco[3.2.1]octan-6-yl]
hydrogen sulfate according to Formula (I) being present in isolated
form.
In another embodiment the present invention relates to
[(2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicylco[3.2.1]octan-6-yl]
hydrogen sulfate according to Formula (I) being present in solid
form.
In a further embodiment the present invention relates to
[(2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicylco[3.2.1]octan-6-yl]
hydrogen sulfate according to Formula (I) being present in
crystalline form.
In a preferred embodiment the present invention relates to a
crystalline form (Form 1) of
[(2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicylco[3.2.1]octan-6-yl]
hydrogen sulfate according to Formula (I) characterized by having a
powder X-ray diffractogram comprising reflections at 2-Theta angles
of:
(9.6.+-.0.2).degree., (11.1.+-.0.2).degree. and
(17.4.+-.0.2).degree., or
(9.6.+-.0.2).degree., (11.1.+-.0.2).degree., (16.4.+-.0.2).degree.
and (17.4.+-.0.2).degree., or
(9.6.+-.0.2).degree., (11.1.+-.0.2).degree., (16.4.+-.0.2).degree.,
(17.4.+-.0.2).degree. and (19.2.+-.0.2).degree., or
(9.6.+-.0.2).degree., (11.1.+-.0.2).degree., (16.4.+-.0.2).degree.,
(17.4.+-.0.2).degree. (19.2.+-.0.2).degree. and
(22.1.+-.0.2).degree., or
(9.6.+-.0.2).degree., (11.1.+-.0.2).degree., (16.4.+-.0.2).degree.,
(17.4.+-.0.2).degree. (19.2.+-.0.2).degree., (22.1.+-.0.2).degree.
and (24.2.+-.0.2).degree., or
(9.6.+-.0.2).degree., (11.1.+-.0.2).degree., (16.4.+-.0.2).degree.,
(16.7.+-.0.2).degree., (17.4.+-.0.2).degree. (19.2.+-.0.2).degree.,
(22.1.+-.0.2).degree. and (24.2.+-.0.2).degree.,
when measured with Cu-Kalpha.sub.1,2 radiation having a wavelength
of 0.15419 nm.
In still another embodiment the present invention relates to a
crystalline form (Form 1) of
[(2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicylco[3.2.1]octan-6-yl]
hydrogen sulfate according to Formula (I) characterized by having a
powder X-ray diffractogram essentially the same as the one
displayed in FIG. 1 of the present invention, when measured with
Cu-Kalpha.sub.1,2 radiation having a wavelength of 0.15419 nm.
In another preferred embodiment the present invention relates to a
crystalline form (Form 2) of
[(2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicylco[3.2.1]octan-6-yl]
hydrogen sulfate according to Formula (I) characterized by having a
powder X-ray diffractogram comprising reflections at 2-Theta angles
of:
(9.3.+-.0.2).degree., (10.1.+-.0.2).degree. and
(16.7.+-.0.2).degree., or
(9.3.+-.0.2).degree., (10.1.+-.0.2).degree., (16.7.+-.0.2).degree.
and (18.8.+-.0.2).degree., or
(9.3.+-.0.2).degree., (10.1.+-.0.2).degree., (16.3.+-.0.2).degree.,
(16.7.+-.0.2).degree. and (18.8.+-.0.2).degree., or
(9.3.+-.0.2).degree., (10.1.+-.0.2).degree., (16.3.+-.0.2).degree.,
(16.7.+-.0.2).degree. (18.8.+-.0.2).degree. and
(24.4.+-.0.2).degree., or
(9.3.+-.0.2).degree., (10.1.+-.0.2).degree., (16.3.+-.0.2).degree.,
(16.7.+-.0.2).degree. (18.8.+-.0.2).degree., (19.5.+-.0.2).degree.
and (24.4.+-.0.2).degree., or
(9.3.+-.0.2).degree., (10.1.+-.0.2).degree., (16.3.+-.0.2).degree.,
(16.7.+-.0.2).degree., (18.8.+-.0.2).degree. (19.5.+-.0.2).degree.,
(23.0.+-.0.2).degree. and (24.4.+-.0.2).degree.,
when measured with Cu-Kalpha.sub.1,2 radiation having a wavelength
of 0.15419 nm.
In still another embodiment the present invention relates to a
crystalline form (Form 2) of
[(2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicylco[3.2.1]octan-6-yl]
hydrogen sulfate according to Formula (I) characterized by having a
powder X-ray diffractogram essentially the same as the one
displayed in FIG. 6 of the present invention, when measured with
Cu-Kalpha.sub.1,2 radiation having a wavelength of 0.15419 nm.
In a further embodiment the present invention relates to a
crystalline form (Form 1) of
[(2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicylco[3.2.1]octan-6-yl]
hydrogen sulfate according to Formula (I) characterized by having a
Fourier transform infrared spectrum comprising peaks at wavenumbers
of:
(3391.+-.2) cm.sup.-1, (1820.+-.2) cm.sup.-1 and (1688.+-.2)
cm.sup.-1, or
(3391.+-.2) cm.sup.-1, (3274.+-.2) cm.sup.-1, (1820.+-.2) cm.sup.-1
and (1688.+-.2) cm.sup.-1, or
(3391.+-.2) cm.sup.-1, (3274.+-.2) cm.sup.-1, (1820.+-.2)
cm.sup.-1, (1688.+-.2) cm.sup.-1 and (1619.+-.2) cm.sup.-1, or
(3391.+-.2) cm.sup.-1, (3274.+-.2) cm.sup.-1, (3214.+-.2)
cm.sup.-1, (1820.+-.2) cm.sup.-1, (1688.+-.2) cm.sup.-1 and
(1619.+-.2) cm.sup.1, or
(3391.+-.2) cm.sup.-1, (3274.+-.2) cm.sup.-1, (3214.+-.2)
cm.sup.-1, (1820.+-.2) cm.sup.-1, (1688.+-.2) cm.sup.-1
(1619.+-.2) cm.sup.-1 and (1304.+-.2) cm.sup.-1, or
(3391.+-.2) cm.sup.-1, (3326.+-.2) cm.sup.-1, (3274.+-.2)
cm.sup.-1, (3214.+-.2) cm.sup.-1, (1820.+-.2) cm.sup.-1,
(1688.+-.2) cm.sup.-1, (1619.+-.2) cm.sup.-1 and (1304.+-.2)
cm.sup.-1, or
(3391.+-.2) cm.sup.-1, (3326.+-.2) cm.sup.-1, (3274.+-.2)
cm.sup.-1, (3214.+-.2) cm.sup.-1, (1820.+-.2) cm.sup.-1,
(1688.+-.2) cm.sup.-1, (1619.+-.2) cm.sup.-1, (1304.+-.2) cm.sup.-1
and (1241.+-.2) cm.sup.-1, or
(3391.+-.2) cm.sup.-1, (3326.+-.2) cm.sup.-1, (3274.+-.2)
cm.sup.-1, (3214.+-.2) cm.sup.-1, (1820.+-.2) cm.sup.-1,
(1688.+-.2) cm.sup.-1, (1619.+-.2) cm.sup.-1, (1304.+-.2)
cm.sup.-1, (1241.+-.2) cm.sup.-1 and (1054.+-.2) cm.sup.-1,
when measured with a diamond ATR cell.
In one embodiment the present invention relates to a crystalline
form (Form 1) of
[(2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicylco[3.2.1]octan-6-yl]
hydrogen sulfate according to Formula (I) characterized by having a
Fourier transform infrared spectrum essentially the same as the one
displayed in FIG. 2 of the present invention, when measured with a
diamond ATR cell.
In a further embodiment the present invention relates to a
crystalline form (Form 2) of
[(2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicylco[3.2.1]octan-6-yl]
hydrogen sulfate according to Formula (I) characterized by having a
Fourier transform infrared spectrum comprising peaks at wavenumbers
of:
(3403.+-.2) cm.sup.-1, (1825.+-.2) cm.sup.-1 and (1686.+-.2)
cm.sup.-1, or
(3403.+-.2) cm.sup.-1, (3277.+-.2) cm.sup.-1, (1825.+-.2) cm.sup.-1
and (1686.+-.2) cm.sup.-1, or
(3403.+-.2) cm.sup.-1, (3277.+-.2) cm.sup.-1, (1825.+-.2)
cm.sup.-1, (1686.+-.2) cm.sup.-1 and (1616.+-.2) cm.sup.-1, or
(3403.+-.2) cm.sup.-1, (3277.+-.2) cm.sup.-1, (3214.+-.2)
cm.sup.-1, (1825.+-.2) cm.sup.-1, (1686.+-.2) cm.sup.-1 and
(1616.+-.2) cm.sup.-1, or
(3403.+-.2) cm.sup.-1, (3277.+-.2) cm.sup.-1, (3214.+-.2)
cm.sup.-1, (1825.+-.2) cm.sup.-1, (1686.+-.2) cm.sup.-1
(1616.+-.2) cm.sup.-1 and (1297.+-.2) cm.sup.-1, or
(3403.+-.2) cm.sup.-1, (3326.+-.2) cm.sup.-1, (3277.+-.2)
cm.sup.-1, (3214.+-.2) cm.sup.-1, (1825.+-.2) cm.sup.-1,
(1686.+-.2) cm.sup.-1, (1616.+-.2) cm.sup.-1 and (1297.+-.2)
cm.sup.-1, or
(3403.+-.2) cm.sup.-1, (3326.+-.2) cm.sup.-1, (3277.+-.2)
cm.sup.-1, (3214.+-.2) cm.sup.-1, (1825.+-.2) cm.sup.-1,
(1686.+-.2) cm.sup.-1, (1616.+-.2) cm.sup.-1, (1297.+-.2) cm.sup.-1
and (1251.+-.2) cm.sup.-1, or
(3403.+-.2) cm.sup.-1, (3326.+-.2) cm.sup.-1, (3277.+-.2)
cm.sup.-1, (3214.+-.2) cm.sup.-1, (1825.+-.2) cm.sup.-1,
(1686.+-.2) cm.sup.-1, (1616.+-.2) cm.sup.-1, (1297.+-.2)
cm.sup.-1, (1251.+-.2) cm.sup.-1 and (1053.+-.2) cm.sup.-1,
when measured with a diamond ATR cell.
In one embodiment the present invention relates to a crystalline
form (Form 2) of
[(2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicylco[3.2.1]octan-6-yl]
hydrogen sulfate according to Formula (I) characterized by having a
Fourier transform infrared spectrum essentially the same as the one
displayed in FIG. 7 of the present invention, when measured with a
diamond ATR cell.
In another embodiment, the present invention relates to a
crystalline form of
[(2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicylco[3.2.1]octan-6-yl]
hydrogen sulfate according to Formula (I) characterized by showing
a weight loss of about 0.5 weight % or less, preferably of about
0.4 weight % or less, more preferably of about 0.3 weight % or less
based on the weight of the crystalline form of avibactam, when
measured with thermogravimetric analysis at a temperature in the
range of from about 25 to 130.degree. C. and a heating rate of
about 10 K/min. Preferably, said crystalline form of
[(2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicylco[3.2.1]octan-6-yl]
hydrogen sulfate is present in crystalline Form 1 of avibactam as
defined above.
Thermal analysis revealed that avibactam free acid of the present
invention is very stable against temperature stress. For example,
avibactam free acid of the present invention shows no thermal event
in the differential scanning calorimetry curve up to a temperature
of at least about 130.degree. C. (see FIG. 3 herein), preferably up
to a temperature of at least about 160.degree. C. and most
preferably up to a temperature of at least about 200.degree. C. In
addition, avibactam of the present invention shows a weight loss of
only about 0.3 weight % up to a temperature of about 130.degree.
C., when measured with thermogravimetric analysis (see FIG. 4)
indicating that avibactam free acid of the present invention is an
anhydrous and non-solvated form of avibactam. In addition,
avibactam free acid of the present invention is also very stable
against moisture. These properties ensure a constant product
quality throughout shelf-life since form conversions upon storage
can be excluded.
Besides being stable against temperature and moisture stress
avibactam free acid of the present invention is also characterized
by excellent powder properties. As can be seen from the scanning
electron microscopic image displayed in FIG. 5a herein avibactam
free acid of the present invention mainly consists of lath-shaped
crystals with a very homogenous particle size distribution
resulting in a free-flowing powder with high bulk density and good
compaction properties. Such powder properties are especially
convenient for pharmaceutical processes including filling processes
into containments, for example into vials e.g. single unit
vials.
Form B of avibactam sodium shows plate-like crystals with diverse
particle sizes (see FIG. 5b herein). Finally, the statement
provided in WO 2011/042560 A1, that anhydrous form D consists of
very small crystals could be confirmed (see FIG. 5c). Such a powder
is usually electrostatically charged and dusting and hence not
preferred for pharmaceutical processing.
Furthermore, the invention relates to a method for the preparation
of [(2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicylco[3.2.1]octan-6-yl]
hydrogen sulfate according to Formula (I) comprising:
(a) Reacting a Compound According to Formula (II)
##STR00003##
wherein M.sup..sym. is N.sym. RR'R''R''' with R, R', R'' and R'''
each being independently selected from hydrogen and alkyl with 1 to
6 carbon atoms, with one or more acid(s) having a pKa<-1;
and
(b) Optionally Isolating at least a part of the Compound According
to Formula (I).
In the course of the present invention an alkyl group is a group
comprising interconnected carbon and hydrogen atoms. An alkyl group
can be a linear or a branched alkyl group.
Linear alkyl groups with 1 to 6 carbons can be methyl (--CH.sub.3),
ethyl (--CH.sub.2CH.sub.3), propyl (--(CH.sub.2).sub.2CH.sub.3),
butyl (--(CH.sub.2).sub.3CH.sub.3), pentyl
(--(CH.sub.2).sub.4CH.sub.3) and hexyl
(--(CH.sub.2).sub.5CH.sub.3). In the present invention linear alkyl
groups with 3 to 6 carbons may be indicated by using the prefix
"n-" e.g. n-propyl, n-butyl, n-pentyl and n-hexyl.
Examples of branched alkyl groups are isopropyl
(--CH(CH.sub.3).sub.2), isobutyl (--CH.sub.2CH(CH.sub.3).sub.2),
tert-butyl (--CH(CH.sub.3).sub.3), isopentyl
(--(CH.sub.2).sub.2CH(CH.sub.3).sub.2) and neohexyl
(--(CH.sub.2).sub.2CH(CH.sub.3).sub.3).
In a preferred embodiment R, R', R'' and R''' each are the same
alkyl group. It is further preferred that R, R', R'' and R''' each
are a linear alkyl group, preferably the same linear alkyl group.
In a particularly preferred embodiment R, R', R'' and R''' each are
n-butyl. Thus, it is particularly preferred that M.sym. is
(Bu).sub.4N.sym..
In step (a) the compound according to Formula (II) is reacted with
an acid having a pK.sub.a value<-1. The smaller the pK.sub.a
value the stronger the acid. Acids having a pK.sub.a value<-1
can be regarded as strong acids.
The one or more acid(s) having a pKa<-1 is preferably selected
from the group consisting of p-toluenesulfonic acid,
p-toluenesulfonic acid monohydrate, p-xylene-2-sulfonic acid
hydrate, benzenesulfonic acid, p-fluorobenzenesulfonic acid,
2,4,6-tri-methylbenzenesulfonic acid, camphor-10-sulfonic acid,
nonafluorobutane-1-sulfonic acid, methanesulfonic acid,
ethanesulfonic acid, 2-hydroxyethanesulfonic acid,
n-propanesulfonic acid, n-butanesulfonic acid, n-hexanesulfonic
acid, cyclopentane-sulfonic acid, trifluoromethanesulfonic acid,
sulfuric acid, hydrochloric acid, hydro-bromic acid, hydroiodic
acid, nitric acid and mixtures of one or more thereof. Particularly
preferred acids are selected from the group of p-toluenesulfonic
acid, p-toluenesulfonic acid monohydrate, hydrochloric acid and
nitric acid. Especially preferred is p-toluenesulfonic acid
monohydrate. Alternatively, particularly preferred is
p-toluenesulfonic acid.
Phosphoric acid, trifluoroacetic acid and formic acid are
preferably not used as acids.
In a preferred embodiment the compound according to Formula (II)
and the acid are reacted in a molecular ratio in the range of from
about 1:1 to 1:1.8, more preferably from about 1:1.01 to 1:1.6,
even more preferably from about 1:1.02 to 1:1.4, in particular from
about 1:1.03 to 1:1.15.
In a preferred embodiment, the reaction is carried out in a solvent
selected from the group consisting of alcohols e.g. ethanol,
n-propanol, isopropanol, isobutanol, 2-butanol, amylalcohol,
methylene chloride, acetone, ethyl acetate, acetonitrile and
mixtures thereof. Preferred solvents are methylene chloride,
isobutanol, acetone and ethanol. Methylene chloride and ethanol are
especially preferred. The solvent preferably comprises less than 2%
w/w, more preferably less than 1% w/w, in particular less than 0.3%
w/w of water. Especially preferred is when the solvent is
substantially free of water.
It is further preferred that the reaction is carried out at a
temperature in the range of from about -10.degree. C. to 35.degree.
C., preferably from about -8.degree. C. to 25.degree. C., even more
preferably from about -6.degree. C. to 15.degree. C., in particular
from about -5.degree. C. to 5.degree. C.
The reaction can preferably be carried out for a period in the
range of from about 5 to 240 minutes, preferably from about 10 to
180 minutes, more preferably from about 15 to 90 minutes, in
particular from about 20 to 45 minutes.
Further, the reaction mixture is preferably subjected to agitation,
mechanical agitation and/or stirring.
In optional step (b) at least part of the compound according to
Formula (I) can be isolated.
Isolating the compound according to Formula (I) can preferably
comprise filtering off the precipitate obtained in step (a).
Filtering off the precipitate can for example be carried out with
the aid of a suction device, a funnel with sieve bottom or filter
paper. Further, the filtered precipitate can preferably be washed,
preferably with the solvent in which the reaction of step (a) was
carried out, in particular with methylene chloride or ethanol.
Further, the compound according to Formula (I) can preferably be
dried. Drying can preferably be carried out under reduced pressure
in the range of from about 5 to 200 mbar. Further, drying can be
carried out at a temperature in the range of from about 10.degree.
C. to 35.degree. C., preferably at about room temperature.
It was unexpectedly found that the above described process yields
avibactam free acid in high purity. For example, avibactam free
acid having a purity of 97% was obtained, although the
tetrabutylammonium salt starting material had a significantly lower
purity of only about 76% (see also example 1.4 herein).
Therefore, the present invention also relates to
[(2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicylco[3.2.1]octan-6-yl]
hydrogen sulfate according to Formula (I) having high purity of at
least 95%, preferably of at least 97%, more preferably of at least
98% and most preferably of at least 99%, such as of at least 99.5%
e.g. 100%. Preferably, said
[(2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicylco[3.2.1]octan-6-yl]
hydrogen sulfate is present in crystalline Form 1 of avibactam as
defined above. The purity may be determined by quantitative 1H-NMR
as disclosed herein and/or by other analytical methods well known
to the skilled person such as high performance liquid
chromatography (HPLC) and mass spectrometry (MS) or any
combinations thereof.
High purity is a prerequisite for an active pharmaceutical
ingredient since by-products do not have the desired
pharmacological activity and on top may be even toxic.
Hence, an additional subject-matter of the present invention
relates to the use of avibactam free acid as defined hereinabove
for the preparation of a pharmaceutical composition.
In a further aspect the present invention relates to a
pharmaceutical composition comprising an effective and/or
predetermined amount of avibactam free acid as defined hereinabove,
one or more alkaline sodium salt(s) and one or more antibacterial
agent(s).
The one or more alkaline sodium salt(s) is preferably selected from
the group consisting of sodium carbonate (Na.sub.2CO.sub.3), sodium
hydrogen carbonate (NaHCO.sub.3), sodium acetate, sodium formiate
and sodium benzoate, wherein sodium carbonate and sodium hydrogen
carbonate are particular preferred and sodium carbonate is most
preferred.
Preferably, the one or more antibacterial agent(s) is a beta-lactam
antibiotic including penams, penems, cephems, carbacephems,
oxacephems, cephamycins, penicillins such as amoxicillin,
ampicillin, azlocillin, mezlocillin, apalcillin, hetacillin,
bacampicillin, carbenicillin, sulbenicillin, ticarcillin,
piperacillin, mecillinam, pivmecillinam, methicillin, ciclacillin,
talampicillin, aspoxicillin, oxacillin, cloxacillin, dicloxacillin,
flucloxacillin, nafcillin, pivampicillin, cephalosporins such as
cephalothin, cephalorodine, cefaclor, cefadroxil, cefamandole,
cefazoline, cephalexin, cephradine, ceftizoxime, cefmenoxime,
cefmetazole, cephaloglycin, cefonicid, cefodizime, cefpirome,
ceftazidime, ceftaroline, ceftaroline fosamil, ceftriaxone,
cefpiramide, cefbuperazone, cefozopran, cefepime, cefoselis,
cefluprenam, cefuzonam, cefpimizole, cefclidin, cefixime,
ceftibuten, cefdinir, cefpodoxime axetil, cefpodoxime proxetil,
cefteram pivoxil, cefetamet pivoxil, cefcapene pivoxil, cefditoren
pivoxil, cefuroxime, cefuroxime axetil, loracarbacef, latamoxef,
carbapenems such as imipenem, meropenem, biapenem, panipenem and
monobactams such as aztreonam and carumonam as well as salts
thereof. Most preferably, the beta-lactam antibiotic is selected
from ceftazidime e.g. in form of its pentahydrate and/or ceftarolin
fosamil e.g. in form of its monoacetate monohydrate.
The pharmaceutical composition of the present invention as defined
above may further comprise one or more pharmaceutically acceptable
excipient(s).
The pharmaceutical composition of the invention can be prepared by
successively filling the single components of the pharmaceutical
composition as defined above into a containment for example into a
vial e.g. a single unit vial.
In a preferred embodiment the pharmaceutical composition of the
present invention as defined above is a sterile powder for
injection, preferably comprised in a single-use vial. Before
application to a patient in need the powder may be reconstituted
for example with sterile water for injection, 0.9% sodium chloride,
5% dextrose, 2.5% dextrose/0.45% sodium chloride or Lactated
Ringer's solution optionally followed by further dilution with a
suitable infusion fluid.
In a further aspect the present invention concerns the
pharmaceutical composition as defined above for use as
medicament.
Another aspect of the present invention relates to the
pharmaceutical composition as defined above for the treatment
and/or prevention of bacterial infections. The bacterial infections
may be caused by beta-lactamase producing bacteria. The bacterial
infection may be selected from complicated intra-abdominal
infections (cIAI) and complicated urinary tract infections
(cUTI).
As already mentioned above avibactam free acid of the present
invention is obtained in high purity when prepared according to the
aforementioned process and therefore may also be advantageously
used as intermediate for the production of pure avibactam
sodium.
Hence, in a further aspect the invention also relates to the use of
[(2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicylco[3.2.1]octan-6-yl]
hydrogen sulfate according to Formula (I) as defined hereinbefore
for the preparation of an avibactam salt, in particular for the
preparation of avibactam sodium.
Another aspect of the invention is a method for the preparation of
the compound according to Formula (III)
##STR00004##
comprising (i) reacting
[(2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicylco[ 3.2.1]octan-6-yl]
hydrogen sulfate according to Formula (I) with one or more sodium
salt(s) of an organic acid having 2 to 8 carbon atoms; and (ii)
optionally isolating at least a part of the compound according to
Formula (III).
The starting material
[(2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicylco[3.2.1]octan-6-yl]
hydrogen sulfate according to Formula (I) can be prepared by the
method described hereinabove for avibactam free acid
preparation.
In the context of the method for the preparation of the compound
according to Fomula (III) the term "organic acid" refers to an
organic compound having a carboxylic acid group. An organic
compound can be referred to as a compound, which apart from carbon,
hydrogen and oxygen atoms further substantially contains nitrogen,
halogens and sulfur atoms. A carboxylic acid group is a group which
can be represented by the following Formula
##STR00005##
Thus, a carboxylic acid group is a group in which a carbon atom is
connected by a covalent double bond to one oxygen atom and by a
further bond to another oxygen atom further otherwise bonded to a
hydrogen atom. The sodium salt of an organic acid can be referred
to as a carboxylic acid group in which the the hydrogen atom
connected to the oxygen of the carboxylic acid group is substituted
by sodium.
In a preferred embodiment the organic acid having 2 to 8 carbon
atoms consists of carbon, hydrogen and oxygen atoms.
The organic acid can have more than one carboxylic acid groups, for
example two carboxylic acid groups like in the case of oxalic acid.
However, it is preferred that the organic acid comprises just one
single carboxylic acid group.
Examples of an organic acid with 2 to 8 carbon atoms, wherein the
organic acid comprises one carboxylic acid group, are acetic acid,
propanoic acid, butyric acid, pivalic acid, hexanoic acid, 2-ethyl
hexanoic acid and octanoic acid.
It is preferred that the organic acid has 4 to 8 carbon atoms, more
preferably 6 to 8 carbon atoms.
In a particularly preferred embodiment the organic acid is hexanoic
acid. The corresponding sodium salt is referred to as sodium
hexanoate.
In an alternative particularly preferred embodiment the organic
acid is 2-ethylhexanoic acid. The corresponding sodium salt is
referred to as sodium 2-ethylhexanoate.
In a preferred embodiment the compound according to Formula (I) and
the sodium salt of an organic acid having 2 to 8 carbon atoms are
reacted in a molecular ratio in the range of from about 1:1.3 to
1:2.5, more preferably from about 1:1.4 to 1:2.4, even more
preferably from about 1:1.6 to 1:2.3, in particular from about
1:1.8 to 1:2.2. The molecular ratio is determined on the basis of
the number of sodium carboxylate groups of the organic acid. Thus,
in case that, for example, disodium salt of the hexanedioic acid is
submitted to the reaction with the compound according to Formula
(I) the molar amount of the organic acid is halved compared to the
monosodium salt of an organic acid with one carboxy group such as
hexanoic acid. The molecular ratio of the compound according to
Formula (I) and the disodium salt of the hexanedioic acid is
accordingly in the range of from about 1:0.65 to 1:1.25, more
preferably from about 1:0.7 to 1:1.2, even more preferably from
about 1:0.8 to 1:1.15, in particular in the range of from about
1:0.9 to 1:1.1.
In a preferred embodiment, the reaction is carried out in an
organic solvent, preferably an organic solvent having a boiling
point in the range of from about 60 to 135.degree. C. at 1.013 bar.
Examples of organic solvents are ethanol, n-propanol, isopropanol,
n-butanol isobutanol, 2-butanol, isoamylalcohol,
2-methyl-2-butanol, ethyl acetate, acetonitrile and mixtures
thereof. Preferred are isopropanol, isobutanol and 2-butanol.
Isobutanol is especially preferred. The solvent preferably
comprises less than 5% w/w, more preferably less than 3% w/w, in
particular less than 0.5% w/w of water. Especially preferred is
when the solvent is substantially free of water.
It is further preferred that the reaction is carried out at a
temperature in the range of from about 60.degree. C. to 135.degree.
C., preferably from about 75.degree. C. to 130.degree. C., in
particular from about 85.degree. C. to 125.degree. C. For example,
the reaction may be carried out at a temperature in the range of
from about 90.degree. C. to 115.degree. C., especially when
isobutanol or 2-butanol is used as solvent.
The reaction can preferably be carried out for a period in the
range of from about 5 to 240 minutes, preferably from about 10 to
180 minutes, more preferably from about 20 to 120 minutes, in
particular from about 30 to 90 minutes.
Further, the reaction mixture is preferably subjected to agitation,
mechanical agitation and/or stirring.
In optional step (ii) at least part of the compound according to
Formula (III) can be isolated.
Isolating the compound according to Formula (III) can preferably
comprise cooling the reaction mixture of step (i) for example to a
temperature in the range of from about -10.degree. C. to 23.degree.
C., preferably from about -7.degree. C. to 15.degree. C., in
particular from about -5.degree. C. to 10.degree. C. In a preferred
embodiment cooling the reaction mixture of step (i) can preferably
be carried out under mechanical movement, such as stirring.
In a preferred embodiment optional step (ii) can preferably
comprise filtering off the precipitate obtained in step (i) or the
precipitate may be filtered off after cooling as mentioned above.
Filtering off the precipitate can for example be carried out with
the aid of a suction device, a funnel with sieve bottom or filter
paper. Further, the filtered precipitate can preferably be washed,
preferably with the solvent in which the reaction of step (i) was
carried out, in particular with isobutanol. Further, the compound
according to Formula (III) can preferably be dried. Drying can be
preferably carried out under reduced pressure in the range of from
about 5 to 200 mbar. Further, drying can be carried out at a
temperature in the range of from about 10 to 35.degree. C.,
preferably at about room temperature.
According to the above described method the compound according to
Formula (III) may be obtained in amorphous form, crystalline form
or as a mixture of amorphous and crystalline forms, preferably it
is obtained in crystalline form. When obtained in crystalline form,
the compound according to Formula (III) is preferably present in
crystalline form A, form B, form C, form D or mixtures thereof.
Most preferably, the compound according to Formula (III) is
obtained as crystalline form C.
In a preferred embodiment the method for the preparation of the
compound according to Formula (III)
##STR00006##
comprises (i) reacting
[(2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicylco[3.2.1]octan-6-yl]
hydrogen sulfate according to Formula (I) with sodium
ethylhexanoate in water-free isobutanol under reflux, and (ii)
optionally isolating at least a part of the compound according to
Formula (III), in particular the compound according to Formula
(III) in crystalline form C.
Generally, as far as the further conditions in step (i) and
optional step (ii) are concerned, the same applies as described
above.
EXAMPLES
The following analytical methods and parameters have been applied
for the generation of analytical data disclosed in the present
invention:
Powder X-Ray Diffraction
Powder X-ray diffraction was performed with a PANalytical X'Pert
PRO diffractometer equipped with a theta/theta coupled goniometer
in transmission geometry, Cu-Kalpha.sub.1,2 radiation (wavelength
0.15419 nm) with a focusing mirror and a solid state PIXcel
detector. Diffractograms were recorded at a tube voltage of 45 kV
and a tube current of 40 mA, applying a stepsize of 0.013.degree.
2-Theta with 40 s per step (255 channels) in the angular range of
2.degree. to 40.degree. 2-Theta at ambient conditions.
Diffractograms were measured at room temperature. A typical
precision of the 2-Theta values is in the range of .+-.0.2.degree.
2-Theta. Thus, the diffraction peak of the crystalline form of
avibactam of the present invention that appears for example at
17.4.degree. 2-Theta can appear between 17.2 and 17.6.degree.
2-Theta on most X-ray diffractometers under standard
conditions.
Fourier Transform Infrared Spectroscopy
Fourier transform infrared spectroscopy (FTIR) was performed with a
MKII Golden Gate.TM. Single Reflection Diamond ATR (attenuated
total reflection) cell with a Bruker Tensor 27 FTIR spectrometer
with 4 cm.sup.-1 resolution. Spectra were recorded at room
temperature. To record a spectrum a spatula tip of the sample was
applied to the surface of the diamond in powder form. Then the
sample was pressed onto the diamond with a sapphire anvil and the
spectrum was recorded. A spectrum of the clean diamond was used as
background spectrum. A typical precision of the wavenumber values
is in the range of about .+-.2 cm.sup.1. Thus, the infrared peak of
the crystalline form of avibactam of the present invention that
appears at 1820 cm.sup.1 can appear between 1818 and 1822 cm.sup.-1
on most infrared spectrometers under standard conditions.
Differential Scanning Calorimetry
Differential scanning calorimetry was performed on a Mettler Toledo
Polymer DSC R instrument. The sample (1.27 mg) was heated in a 40
microL aluminium pan with pierced aluminium lid from 25 to
160.degree. C. at a rate of 10 K/min. Nitrogen (purge rate 50
mL/min) was used as purge gas.
Thermogravimetric Analysis
Thermogravimetric analysis (TGA) was performed on a Mettler TGA/DSC
1 instrument. The sample (6.30 mg) was heated in a 100 microL
aluminum pan closed with an aluminum lid. The lid was automatically
pierced at the beginning of the measurement. The sample was heated
from 25 to 200.degree. C. at a rate of 10 K/min. Nitrogen (purge
rate 50 mL/min) was used as purge gas.
Scanning Electron Microscopy
Scanning electron microscopic images were recorded with a Hitachi
TM3030Plus Tabletop scanning electron microscope. The samples were
prepared on a carbon disk and observed in a mixed secondary
electron/back scattering electron (SE/BSE) mode with charge-up
reduction applying an accelerating voltage of 5 kV.
Nuclear Magnetic Resonance
Nuclear magnetic resonance spectra were acquired on a Bruker 400
MHz spectrometer. Chemical shifts 6 are expressed as parts per
million (ppm) and were referenced to residual solvent signals at
2.50 ppm (DMSO-D6) for the proton NMR spectra as well as to the
solvent signal 39.52 ppm (DMSO-D6) for 13C NMR spectra. Coupling
constants are quoted in Hz. TCNB (2,3,5,6-tetrachloronitrobenzene)
was used as internal standard for quantitative 1H-NMR
measurements.
The following non-limiting examples are illustrative for the
disclosure.
Example 1: Preparation of
[(2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicylco[3.2.1]octan-6-yl]
Hydrogen Sulfate (Avibactam)
Example 1.1
Avibactam tetrabutylammonium salt (255 mg, 0.50 mmol, prepared
according to the procedure disclosed in example 4a of U.S. Pat. No.
8,969,566 B2) was dissolved in 2.5 mL ethanol and cooled to
0-5.degree. C. Under stirring p-toluenesulfonic acid monohydrate
(102 mg, 0.53 mmol) was added and a white precipitate formed. After
stirring for 30 min at 0-5.degree. C., the solid was filtered off,
washed with ethanol and dried under vacuum at room temperature to
yield 90 mg of avibactam free acid in polymorphic Form 1 (Yield:
68%, Purity: 100% by QNMR).
1H-NMR (400 MHz, DMSO-D6), .delta.[ppm]: 7.44 (bs, 1H,
NH.sub.amide), 7.29 (bs, 1H, NH.sub.amide), 6.97 (bs, SO.sub.3H),
3.98 (s, 1H, CH), 3.69 (d, J=5.1 Hz, 1H, CH), 3.03 (d, J=10.5 Hz,
1H, CH.sub.2), 2.93 (d, J=11.4 Hz, 1H, CH.sub.2), 2.13-1.98 (m, 1H,
CH.sub.2), 1.91-1.75 (m, 1H, CH.sub.2) 1.72-1.54 (m, 2H,
CH.sub.2)
.sup.13C-NMR (400 MHz, DMSO-D6), .delta.[ppm]: 171.5, 165.8, 59.6,
57.5, 47.0, 20.5, 18.1
The powder X-ray diffractogram of the obtained material is
displayed in FIG. 1 and the corresponding reflection list is
provided in table 1.
TABLE-US-00001 TABLE 1 Reflections in the range of 2.0 to
30.0.degree. 2-Theta and corresponding relative intensities Angle
Relative Intensity [.+-.0.2 .degree.2-Theta] [%] 9.6 7 11.1 16 14.2
2 16.4 25 16.7 8 17.4 100 19.2 15 19.7 3 20.2 6 20.8 3 21.8 3 22.1
21 22.4 11 23.5 4 24.2 19 24.8 2 25.6 1 26.2 4 26.8 3 27.7 3 28.3 8
29.1 5
The Fourier transform infrared spectrum of the obtained material is
displayed in FIG. 2 and the corresponding peak list is provided in
table 2.
TABLE-US-00002 TABLE 2 FTIR peaks in the range of 4000 and 600
cm.sup.-1 Wavenumber [.+-.2 cm.sup.-1] 3391 3326 3274 3214 3120
2966 1820 1688 1619 1466 1447 1408 1373 1304 1275 1241 1176 1143
1109 1074 1054 1021 977 927 898 867 848 810 787 743 723 662 608
Example 1.2
Avibactam tetrabutylammonium salt (250 mg, 0.49 mmol, prepared
according to the procedure disclosed in example 4a of U.S. Pat. No.
8,969,566 B2) was dissolved in methylene chloride (2.5 mL) and
cooled to 0-5.degree. C. Under stirring HNO.sub.3 (65%, 33 microL,
0.51 mmol) was added. After stirring for 30 min at 0-5.degree. C.,
the white precipitate formed was filtered off, washed with
methylene chloride (1 mL) and dried under vacuum at room
temperature to yield 79 mg of avibactam in form of the free acid
(Yield: 60%, Purity: 100% by QNMR)
Example 1.3
Avibactam tetrabutylammonium salt (250 mg, 0.49 mmol, prepared
according to the procedure disclosed in example 4a of U.S. Pat. No.
8,969,566 B2) was dissolved in methylene chloride (2.5 mL) and
cooled to 0-5.degree. C. Under stirring conc. HCl (37%; 42 microL,
0.51 mmol) was added. After stirring for 30 min at 0-5.degree. C.,
the white precipitate formed was filtered off, washed with
methylene chloride (1 mL) and dried under vacuum at room
temperature to yield 75 mg of avibactam in form of the free acid
(Yield: 55%, Purity: 97% by QNMR).
Example 1.4: Purification Effect
Avibactam tetrabutylammonium salt (2.0 g, Purity: 76% by QNMR, 3.00
mmol, prepared according to the procedure disclosed in example 4a
of U.S. Pat. No. 8,969,566 B2) was dissolved in methylene chloride
(20 mL) and cooled to 0-5.degree. C. Under stirring
p-toluenesulfonic acid monohydrate (0.80 g, 4.15 mmol) was added
and a white precipitate formed. After stirring for 30 min at
0-5.degree. C., the solid was filtered off, washed with methylene
chloride and dried under vacuum at room temperature to yield 0.73 g
(Yield: 89%, Purity: 97% by QNMR).
Example 1.5
Avibactam tetrabutylammonium salt (251 mg, 0.49 mmol, prepared
according to the procedure disclosed in example 4a of U.S. Pat. No.
8,969,566 B2) was dissolved in 4.0 mL isobutanol and cooled to
0-5.degree. C. Under stirring p-toluenesulfonic acid monohydrate
(105 mg, 0.53 mmol) was added and a white precipitate formed. After
stirring for 30 min at 0-5.degree. C., the solid was filtered off,
washed with isobutanol and dried under vacuum at room temperature
to yield 115 mg of avibactam free acid in polymorphic Form 2
(Yield: 87%, Purity: 92% by QNMR).
1H-NMR (400 MHz, DMSO-D6), .delta.[ppm]: 7.45 (bs, 1H,
NH.sub.amide), 7.26 (bs, 1H, NH.sub.amide), 6.97 (bs, 50.sub.3H),
3.98 (s, 1H, CH), 3.70 (d, J=5.1 Hz, 1H, CH), 3.03 (d, J=10.5 Hz,
1H, CH.sub.2), 2.93 (d, J=11.4 Hz, 1H, CH.sub.2), 2.13-1.98 (m, 1H,
CH.sub.2), 1.91-1.75 (m, 1H, CH.sub.2) 1.72-1.54 (m, 2H,
CH.sub.2)
The powder X-ray diffractogram of the obtained material is
displayed in FIG. 6 and the corresponding reflection list is
provided in table 3.
TABLE-US-00003 TABLE 3 Reflections in the range of 2.0 to
30.0.degree. 2-Theta and corresponding relative intensities Angle
Relative Intensity [.+-.0.2 .degree.2-Theta] [%] 9.3 30 10.1 36
13.4 3 16.3 40 16.7 100 18.8 46 19.5 19 20.3 4 21.8 4 23.0 15 24.4
22 24.8 5 25.7 13 26.8 4 29.6 9
The Fourier transform infrared spectrum of the obtained material is
displayed in FIG. 7 and the corresponding peak list is provided in
table 4.
TABLE-US-00004 TABLE 4 FTIR peaks in the range of 4000 and 600
cm.sup.-1 Wavenumber [.+-.2 cm.sup.-1] 3403 3326 3277 3214 2958
1825 1686 1616 1464 1413 1325 1297 1276 1251 1184 1145 1074 1053
979 927 868 846 809 746 718 663 611
Comparative Example 1
To a stirred solution of avibactam tetrabutylammonium salt (20.0 g,
purity: 76% by QNMR, 30.0 mmol, prepared according to the procedure
disclosed in example 4a of U.S. Pat. No. 8,969,566 B2) in ethanol
(126 mL) a solution of sodium 2-ethylhexanoate (13.12 g, 78.9 mmol)
in ethanol was added at 30.degree. C. over five hours. The solution
was seeded twice with avibactam sodium polymorphic form B (prepared
according to the procedure disclosed in WO 2011/042560 A1) during
addition of the sodium 2-ethylhexanoate solution. The suspension
was stirred an additional 12 hours at 30.degree. C. Subsequently
the suspension was cooled to 0.degree. C. for 2 hours, filtered and
washed with ethanol at 0-5.degree. C. The crystals were dried under
reduced pressure at 25.degree. C. for 18 hours and 7.45 g of
avibactam sodium polymorphic form B was obtained (Purity: 74% by
QNMR, Yield: 64%)
Reference Example 1
Avibactam tetrabutylammonium salt (100 mg, 0.197 mmol, prepared
according to the procedure disclosed in example 4a of U.S. Pat. No.
8,969,566 B2) was dissolved in methylene chloride (1 mL) and cooled
to 0-5.degree. C. Under stirring trifluoroacetic acid (18 microL,
0.237 mmol) was added. The solution neither became turbid nor a
solid precipitated.
Example 2: Synthesis of the Sodium Salt of
[(2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicylco[3.2.1]octan-6-yl]
Hydrogen Sulfate (Avibactam Sodium)
##STR00007##
Example 2.1
Avibactam free acid (100 mg, 0.377 mmol, prepared according to one
of the procedures described under example 1 herein) was suspended
in isobutanol (2 mL). The suspension was heated under stirring to
reflux temperature and a solution of sodium 2-ethylhexanoate (126
mg, 0.754 mmol) in isobutanol (2 mL) was added within 20 seconds.
After refluxing the reaction mixture for 50 min, the suspension was
cooled in an ice bath, the white solid was filtered off and washed
with isobutanol to yield (84 mg, Yield: 77%) of avibactam sodium.
Powder X-ray diffraction confirmed that avibactam sodium form C was
obtained.
Example 2.2
Avibactam free acid (100 mg, 0.377 mmol, prepared according to one
of the procedures described under example 1 herein) was suspended
in isobutanol (2 mL). A solution of sodium ethylhexanoate (63 mg,
0.377 mmol) in isobutanol (2 mL) was added within 30 min under
stirring. After, the suspension was stirred at room temperature
overnight (approximately 16 hours), the white solid was filtered
off and washed with isobutanol to obtain (32 mg, Yield: 29%) of
avibactam sodium. Powder X-ray diffraction confirmed that avibactam
sodium form D was obtained.
Example 2.3
Avibactam free acid (100 mg, 0.377 mmol, prepared according to one
of the procedures described under example 1 herein) was suspended
in a mixture of isobutanol (2 mL) and methanol (2 mL). The
suspension was heated under stirring (oil bath temperature:
80.degree. C.) and a solution of sodium 2-ethylhexanoate (126 mg,
0.754 mmol) in isobutanol (2 mL) was added within 20 seconds. After
the suspension was stirred at 80.degree. C. overnight
(approximately 16 hours), the reaction vessel was cooled in an ice
bath, the white solid was filtered off and washed with isobutanol
to yield (65 mg, Yield: 60%) of avibactam sodium. Powder X-ray
diffraction confirmed that avibactam sodium form B was
obtained.
Reference Example 2
Avibactam free acid (100 mg, 0.38 mmol, prepared according to one
of the procedures described in example 1 herein) was suspended in
isobutanol (2 mL). The suspension was heated under stirring to
reflux and a solution of sodium ethylhexanoate (63 mg, 0.38 mmol)
in isobutanol (2 mL) was added within 60 seconds. A yellow
suspension was formed within 7 minutes. After 2 hours, the solid
was filtered off and washed. A composition containing avibactam
sodium and undefined degradation products was obtained.
* * * * *